ASSESSMENT OF 2 PENICILLINS PLUS BETA-LACTAMASE INHIBITORS VERSUS CEFOTAXIME IN TREATMENT OF MURINE KLEBSIELLA-PNEUMONIAE INFECTIONS

The in vivo efficacies of piperacillin, piperacillin plus tazobactam, ticarcillin, ticarcillin plus clavulanic acid, piperacillin plus clavu lanic acid, and cefotaxime were compared in a mouse model of pneumonia induced by the SHV-1 beta-lactamase-producer Klebsiella pneumoniae. E ach antibiotic was injected either once intraperitoneally at 24 h post infection or at repeated times during 24 h. The efficacies of the drug s and therapeutic protocols were assessed by counting viable bacteria recovered from the lungs of mice sacrificed at selected times, No emer gence of beta-lactam-resistant organisms was detected, Ticarcillin at 300 mg/kg was ineffective, Repeated injections of piperacillin at 300 mg/kg, either alone or in combination with tazobactam (8:1), led to a significant decrease in bacterial counts, but this was followed by bac terial regrowth. The pharmacokinetic analysis demonstrated that this s hort-lasting antibacterial effect was not due to a failure of piperaci llin and/or tazobactam to penetrate the lungs, The combinations of tic arcillin at 300 mg/kg plus clavulanic acid (15:1) and piperacillin at 300 mg/kg plus tazobactam (4:1) were proven to be effective in that th ey decreased the bacterial burden in the lungs from 10(5) to <10(3) CF U, This dose effect of tazobactam can be explained by its dose-depende nt penetration in the lungs, Cefotaxime at 100 mg/kg and the combinati on of piperacillin (slightly hydrolyzed by SHV-1) at 300 mg/kg plus cl avulanic acid (15:1) led to the best efficacy, Both of these treatment s induced a decrease in bacterial counts of nearly 4 log(10) units, Th e survival rates correlated,vith the quantitative measurements of in v ivo bacterial killing, These experimental results obtained from the re stricted animal model used here may help in the design of further prot ocols for clinical trials.